Serelaxin improves the therapeutic efficacy of RXFP1-expressing human amnion epithelial cells in experimental allergic airway disease

Abstract

Current asthma therapies primarily target airway inflammation (AI) and suppress episodes of airway hyperresponsiveness (AHR) but fail to treat airway remodelling (AWR), which can develop independently of AI and contribute to irreversible airway obstruction. The present study compared the anti-remodelling and therapeutic efficacy of human bone marrow-derived mesenchymal stem cells (MSCs) to that of human amnion epithelial stem cells (AECs) in the setting of chronic allergic airways disease (AAD), in the absence or presence of an anti-fibrotic (serelaxin; RLX). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD, were either vehicle-treated (OVA alone) or treated with MSCs or AECs alone [intranasally (i.n.)-administered with 1×10 cells once weekly], RLX alone (i.n.-administered with 0.8 mg/ml daily) or a combination of MSCs or AECs and RLX from weeks 9-11 (n=6/group). Measures of AI, AWR and AHR were then assessed. OVA alone exacerbated AI, epithelial damage/thickness, sub-epithelial extracellular matrix (ECM) and total collagen deposition, markers of collagen turnover and AHR compared with that in saline-treated counterparts (all P<0.01 compared with saline-treated controls). RLX or AECs (but not MSCs) alone normalized epithelial thickness and partially diminished the OVA-induced fibrosis and AHR by ∼40-50% (all P<0.05 compared with OVA alone). Furthermore, the combination treatments normalized epithelial thickness, measures of fibrosis and AHR to that in normal mice, and significantly decreased AI. Although AECs alone demonstrated greater protection against the AAD-induced AI, AWR and AHR, compared with that of MSCs alone, combining RLX with MSCs or AECs reversed airway fibrosis and AHR to an even greater extent.

Intranasal administration of mesenchymoangioblast‐derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease

“…The key finding of this study was that MCA‐MSCs, when given intranasally, reversed fibrosis and reverted AHR to levels measured in uninjured mice. These findings are consistent with previous studies that show that therapies that were able to abrogate AWR, specifically aberrant airway collagen deposition and TGF‐β1 levels, were seen to reverse AHR (15, 28, 32, 41). AHR is driven by airway obstruction, which can be caused by mucus plugging from goblet cell metaplasia (50) and by epithelial thickening (38).…”

“…Twenty‐four hours after the establishment of chronic AAD (on d 64), subgroups of Ova‐ or Sal‐sensitized/challenged mice ( n = 8 mice/group) underwent IV or IN administration of MCA‐MSCs. In all cases, a 14‐d treatment period (from d 64 to 77) was chosen to replicate the time frame used to evaluate the intranasally delivered effects of other stem cells, such as human bone marrow–derived (stromal) MSCs (15, 28) and human amnion epithelial cells (28), in the Ova‐induced chronic model of AAD.…”

“…For IV administration of MCA‐MSCs, 1 × 10 7 cells were resuspended in 2 ml PBS. Mice were restrained in a Perspex restrainer (Perspex Distribution, Chelmsford, United Kingdom), and 1 × 10 6 cells/200 μl PBS were injected into the tail vein of Sal‐ or Ova‐sensitized/challenged mice, which is a commonly used cell concentration delivered to mice (13, 15, 20, 28). For IN administration of MCA‐MSCs, 1 × 10 7 cells were resuspended in 0.5 ml of PBS.…”

Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog?

“…Similarly, hAEC reportedly exerted immunomodulatory effects in the developing lungs such that delivery of hAECs attenuated pulmonary inflammation in sheep fetuses that were challenged with lipopolysaccharide . In a murine model of hyperoxia induced neonatal lung injury, hAEC also reversed alveolar simplification . When media conditioned by hCMSC from preterm babies were cocultured with fetal rat lungs (E14.5–15.5), ex vivo lung growth was markedly accelerated after 72‐hour culture .…”

Novel Anti-fibrotic Therapies

“…Recent studies also showed efficacy of intranasal relaxin administration in allergic airway disease and cigarette smoke induced lung damage (Royce et al, 2014; Pini et al, 2016). In an exciting development, relaxin and bone marrow-derived mesenchymal stem cells or amnionic epithelial stem cells were found to be synergistic in the treatment of established airway disease (Royce et al, 2015, 2016). The mechanism for this effect is currently under investigation, but appears to be related to the matrix remodeling and anti-TGFβ effects of relaxin promoting a favorable environment for the establishment of stem cell residency in the damaged tissue (Samuel et al, 2016b).…”